Substituted N-(1,4,5,6,-tetrahydro-cyclopentapyrazol-3-yl) derivatives, their production and use as pharmaceutical agents

ABSTRACT

Substituted N-(1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl) derivatives, their production, as well as intermediate products for their production, and the use as pharmaceutical agents for treating various diseases are described.

[0001] The invention relates to substitutedN-(1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl) derivatives, theirproduction and use as pharmaceutical agents for treating variousdiseases.

[0002] Known from DE 198 54 081 A1 or WO 00/31066 are substitutedN-pyrazolyl-phenoxynicotinic acid-(thio)amides that are used asherbicides. These compounds clearly differ structurally from thecompounds according to the invention, however.

[0003] From WO 01/12189, 3(5)-amino-pyrazole derivatives and their useas pharmaceutical agents, especially for treating cancer andcell-proliferative diseases, are known. These compounds also differ fromthe compounds according to the invention by their structure, especiallyon the pyrazole ring.

[0004] There is still a great need for effective pharmaceutical agentsfor treating cancer and other cell-proliferative diseases.

[0005] It has now been found that compounds of general formula I

[0006] in which

[0007] R¹ stands for linear or branched C₁-C₆-alkyl, C₂-C₆-alkenyl,C₂-C₆-alkinyl, C₁-C₆-alkoxy, C₁-C₆-alkylthio or C₃-C₁₂-cycloalkyl,C₃-C₁₂-cycloalkenyl, C₃-C₁₂-heterocycloalkyl, C₃-C₁₂-heterocycloalkenyl,aryl or heteroaryl, which optionally can be substituted in one or moreplaces in the same way or differently,

[0008] R² and R³ are the same or different and stand for hydrogen,linear or branched C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl orC₁-C₆-alkoxy, which optionally can be substituted in one or more placesin the same way or differently,

[0009] R⁴ and R⁵ are the same or different and stand for hydrogen,halogen, linear or branched C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl orC₁-C₆-alkoxy, which optionally can be substituted in one or more placesin the same way or differently, or together stand for a carbonyl group,or together form a cyclic five- or six-ring-acetal with O,O; N,O; O,S;or S,S, which optionally can be substituted with C₁-C₆-alkyl, or

[0010] R² and R⁴ together form a C₃-C₁₂-cycloalkyl ring or aC₃-C₁₂-cycloalkenyl ring, which optionally can be substituted in one ormore places in the same way or differently,

[0011] R and R⁷ are the same or different and stand for hydrogen, linearor branched C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkinyl, whichoptionally can be substituted in one or more places in the same way ordifferently, or together form a C₃-C₁₂-cycloalkyl ring or aC₃-C₁₂-cycloalkenyl ring, which optionally can be substituted in one ormore places in the same way or differently, or

[0012] R⁵ and R⁶ optionally together form a double bond, or

[0013] R⁵ und R⁶ together form a C₃-C₁₂-cycloalkyl ring or aC₃-C₁₂-cycloalkenyl ring, which optionally can be substituted in one ormore places in the same way or differently,

[0014] T stands for —CH₂—, —O—, —CH₂═CH₂—, —CH≡CH—, —CH₂—O—CH₂—,—CH₂—O—, —O—CH₂— or ═CO, and

[0015] n stands for 0-6, as well as tautomers, isomers and saltsthereof.

[0016] Alkyl is defined in each case as a straight-chain or branchedalkyl radical, such as, for example, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl or hexyl.

[0017] Alkoxy is defined in each case as a straight-chain or branchedalkoxy radical, such as, for example, methyloxy, ethyloxy, propyloxy,isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy,pentyloxy, isopentyloxy or hexyloxy.

[0018] Alkythio is defined in each case as a straight-chain or branchedalkylthio radical, such as, for example, methylthio, ethylthio,propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio,tert-butylthio, pentylthio, isopentylthio or hexylthio.

[0019] Cycloalkyls are defined as monocyclic alkyl rings, such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl,cyclooctyl, cyclononyl or cyclodecyl, but also bicyclic rings ortricyclic rings, such as, for example, norbornyl, adamantanyl, etc.

[0020] Cycloalkenyl is defined in each case as cyclobutenyl,cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenylor cyclodecenyl, whereby the linkage can be carried out both to thedouble bond and to the single bonds.

[0021] Halogen is defined in each case as fluorine, chlorine, bromine oriodine.

[0022] Alkenyl is defined in each case as a straight-chain or branchedalkenyl radical that contains 2-6, preferably 2-4, C atoms. For example,the following radicals can be mentioned: vinyl, propen-1-yl,propen-2-yl, but-1-en-1-yl, but-1-en-2-yl, but-2-en-1-yl, but-2-en-2-yl,2-methyl-prop-2-en-1-yl, 2-methyl-prop-1-en-1-yl, but-1-en-3-yl,but-3-en-1-yl, and allyl.

[0023] Alkinyl is defined in each case as a straight-chain or branchedalkinyl radical that contains 2-6, preferably 2-4, C atoms. For example,the following radicals can be mentioned: acetylene, propin-1-yl,propin-3-yl, but-1-in-1-yl, but-1-in-4-yl, but-2-in-1-yl, but-1-in-3-yl,etc.

[0024] The aryl radical in each case comprises 3-12 carbon atoms, andcan be benzocondensed in each case.

[0025] For example, there can be mentioned: cyclopropenyl,cyclopentadienyl, phenyl, tropyl, cyclooctadienyl, indenyl, naphthyl,azulenyl, biphenyl, fluorenyl, anthracenyl, etc.

[0026] The heteroaryl radical in each case comprises 3-16 ring atoms,and instead of carbon, the radical can contain one or more heteroatomsthat are the same or different, such as oxygen, nitrogen or sulfur inthe ring, and can be monocyclic, bicyclic or tricyclic, and in additionin each case can be benzocondensed.

[0027] For example, there can be mentioned:

[0028] Thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, etc. and benzo derivatives thereof, such as, e.g.,benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, indazolyl,indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, triazinyl, etc. and benzo derivatives thereof, such as, e.g.,quinolyl, isoquinolyl, etc.; or oxepinyl, azocinyl, indolizinyl,indolyl, isoindolyl, indazolyl, benzimidazolyl, purinyl, etc. and benzoderivatives thereof; or quinolinyl, isoquinolinyl, cinnolinyl,phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl,carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,xanthenyl, etc.

[0029] Heterocycloalkyl stands for an alkyl ring that comprises 3-12carbon atoms and that instead of carbon contains one or more heteoratomsthat are the same or different, such as, e.g., oxygen, sulfur ornitrogen.

[0030] As heterocycloalkyls, there can be mentioned, e.g.: oxiranyl,oxethanyl, aziridinyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl,dioxolanyl, imidazolidinyl, pyrazolidinyl, dioxanyl, piperidinyl,morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl,quinuclidinyl, etc.

[0031] Heterocycloalkenyl stands for an alkyl ring that comprises 3-12carbon atoms and that instead of carbon contains one or more heteroatomsthat are the same or different, such as, e.g., oxygen, sulfur ornitrogen, and that is partially saturated.

[0032] As heterocycloalkenyls, there can be mentioned, e.g.: pyran,thiine, dihydroazete, etc.

[0033] Cyclic acetal stands for a ring, such as, e.g.,

[0034] which optionally can be substituted with a C₁-C₆-alkyl group.

[0035] The aryl radical and the heteroaryl radical can be substituted ineach case in one or more places in the same way or differently withhydroxy, halogen, amino, C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio,halo-C₁₋₆-alkyl, halo-C₁₋₆-alkoxy, C₁₋₆-alkoxycarbonyl, cyano, nitro,C₁₋₆-alkylsulfanyl, C₁₋₆-alkylsulfinyl, C₁₋₆-alkylsulfonyl, or with thegroup —C(O)C₁₋₆-alkyl, —NHC₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, —CONH₂,—CONHC₁₋₆-alkyl or —CON-di-C₁₋₆-alkyl, or can be substituted withanother aryl or heteroaryl radical, which optionally itself can besubstituted in one or more places in the same way or differently withhydroxy, halogen, amino, C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio,halo-C₁₋₆-alkyl, halo-C₁₋₆-alkoxy, C₁₋₆-alkoxycarbonyl, cyano, nitro,C₁₋₆-alkylcarbonyl, C₁₋₆-alkylsulfanyl, C₁₋₆-alkylsulfinyl,C₁₋₆-alkylsulfonyl, or with the group —C(O)C₁₋₆-alkyl, —NHC₁₋₆-alkyl,—N-di-C₁₋₆-alkyl, —CONH₂, —CONHC₁₋₆-alkyl or —CON-di-C₁₋₆-alkyl.

[0036] If an acid group is included, the physiologically compatiblesalts of organic and inorganic bases are suitable as salts, such as, forexample, the readily soluble alkali salts and alkaline-earth salts aswell as N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine,1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol,tris-hydroxy-methyl-amino-methane, aminopropanediol, Sovak base, and1-amino-2,3,4-butanetriol.

[0037] If a basic group is included, the Physiologically compatiblesalts of organic and inorganic acids are suitable, such as hydrochloricacid, sulfuric acid, phosphoric acid, citric acid, tartaric acid,fumaric acid, i.a.

[0038] Those compounds of general formula I, in which

[0039] R¹ stands for linear or branched C₁-C₆-alkyl, C₂-C₆-alkenyl,C₂-C₆-alkinyl, C₁-C₆-alkoxy, C₁-C₆-alkylthio or C₃-C₁₂-cycloalkyl,C₃-C₁₂-cycloalkenyl, C₃-C₁₂-heterocycloalkyl, C₃-C₁₂-heterocycloalkenyl,aryl or heteroaryl, which optionally can be substituted in one or moreplaces in the same way or differently with hydroxy, halogen, amino,C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, halo-C₁₋₆-alkyl,halo-C₁₋₆-alkoxy, C₁₋₆-alkoxycarbonyl, cyano, nitro, C₁₋₆-alkylsulfanyl,C₁₋₆-alkylsulfinyl, C₁₋₆-alkylsulfonyl, or with the group—C(O)C₁₋₆-alkyl, —NHC₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, —CONH₂,—CONHC₁₋₆-alkyl or —CON-di-C₁₋₆-alkyl, or can be substituted withanother aryl radical or heteroaryl radical that optionally itself can besubstituted in one or more places in the same way or differently,

[0040] R² and R³ are the same or different and stand for hydrogen,linear or branched C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl orC₁-C₆-alkoxy, which optionally can be substituted in one or more placesin the same way or differently with hydroxy, halogen, amino,C₁₋₆-alkoxy, or with the group —NHC₁₋₆-alkyl or —N-di-C₁₋₆-alkyl,

[0041] R⁴ and R⁵ are the same or different and stand for hydrogen,halogen, linear or branched C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl orC₁-C₆-alkoxy, which optionally can be substituted in one or more placesin the same way or differently with hydroxy, halogen, amino,C₁₋₆-alkoxy, or with the group —NHC₁₋₆-alkyl or —N-di-C₁₋₆-alkyl, ortogether stand for a carbonyl group, or together form a cyclic five- orsix-ring-acetal of the structure

[0042]  or

[0043] R² and R⁴ together form a C₃-C₁₂-cycloalkyl ring or aC₃-C₁₂-cycloalkenyl ring, which optionally can be substituted in one ormore places in the same way or differently with hydroxy, halogen, amino,C₁₋₆-alkoxy, or with the group —NHC₁₋₆-alkyl or —N-di-C₁₋₆-alkyl, or

[0044] R³ and R⁵ together form a C₃-C₁₂-cycloalkyl ring or aC₃-C₁₂-cycloalkenyl ring, which optionally can be substituted in one ormore places in the same way or differently with hydroxy, halogen, amino,C₁₋₆-alkoxy, or with the group —NHC₁₋₆-alkyl or —N-di-C₁₋₆-alkyl,

[0045] R⁶ and R⁷ are the same or different and stand for hydrogen,linear or branched C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkinyl, whichoptionally can be substituted in one or more places in the same way ordifferently with hydroxy, halogen, amino, C₁₋₆-alkoxy, or with the group—NHC₁₋₆-alkyl or —N-di-C₁₋₆-alkyl, or together form a C₃-C₁₂-cycloalkylring or a C₃-C₁₂-cycloalkenyl ring, which optionally can be substitutedin one or more places in the same way or differently with hydroxy,halogen, amino, C₁₋₆-alkoxy, or with the group —NHC₁₋₆-alkyl or—N-di-C₁₋₆-alkyl, or

[0046] R⁵ and R⁶ optionally together form a double bond,

[0047] T stands for —CH₂—, —O—, —CH₂═CH₂—, —CH≡CH—, —CH₂—O—CH₂—,—CH₂—O—, —O—CH₂— or ═CO, and

[0048] n stands for 0-6, as well as tautomers, isomers and saltsthereof,

[0049] have proven especially valuable.

[0050] Those compounds of general formula I, in which

[0051] R¹ stands for linear or branched C₁-C₆-alkyl, C₂-C₆-alkenyl,C₂-C₆-alkinyl, C₁-C₆-alkoxy, C₁-C₆-alkylthio or C₃-C₁₂-cycloalkyl,C₃-C₁₂-cycloalkenyl, C₃-C₁₂-heterocycloalkyl, C₃-C₁₂-heterocycloalkenyl,aryl or heteroaryl, which optionally can be substituted in one or moreplaces in the same way or differently with hydroxy, halogen, amino,C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, halo-C₁₋₆-alkyl,halo-C₁₋₆-alkoxy, C₁₋₆-alkoxycarbonyl, cyano, nitro, C₁₋₆-alkylsulfanyl,C₁₋₆-alkylsulfinyl, C₁₋₆-alkylsulfonyl, or with the group—C(O)C₁₋₆-alkyl, —NHC₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, —CONH₂,—CONHC₁₋₆-alkyl or —CON-di-C₁₋₆-alkyl, or can be substituted withanother aryl or heteroaryl radical, which optionally itself can besubstituted in one or more places in the same way or differently withhydroxy, halogen, amino, C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio,halo-C₁₋₆-alkyl, halo-C₁₋₆-alkoxy, C₁₋₆-alkoxycarbonyl, cyano, nitro,C₁₋₆-alkylcarbonyl, C₁₋₆-alkylsulfanyl, C₁₋₆-alkylsulfinyl,C₁₋₆-alkylsulfonyl, or with the group —C(O)C₁₋₆-alkyl, —NHC₁₋₆-alkyl,—N-di-C₁₋₆-alkyl, —CONH₂, —CONHC₁₋₆-alkyl or —CON-di-C₁₋₆-alkyl,

[0052] R² and R³ are the same or different and stand for hydrogen,linear or branched C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl orC₁-C₆-alkoxy, which optionally can be substituted in one or more placesin the same way or differently with hydroxy, halogen, amino,C₁₋₆-alkoxy, or with the group —NHC₁₋₆-alkyl or —N-di-C₁₋₆-alkyl,

[0053] R⁴ and R⁵ are the same or different and stand for hydrogen,halogen, linear or branched C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl orC₁-C₆-alkoxy, which optionally can be substituted in one or more placesin the same way or differently with hydroxy, halogen, amino,C₁₋₆-alkoxy, or with the group —NHC₁₋₆-alkyl or —N-di-C₁₋₆-alkyl, ortogether stand for a carbonyl group, or together form a cyclic five- orsix-ring-acetal of the structure

[0054]  or

[0055] R² and R⁴ together form a C₃-C₁₂-cycloalkyl ring or aC₃-C₁₂-cycloalkenyl ring, which optionally can be substituted in one ormore places in the same way or differently with hydroxy, halogen, amino,C₁₋₆-alkoxy, or with the group —NHC₁₋₆-alkyl or —N-di-C₁₋₆-alkyl, or

[0056] R³ and R⁵ together form a C₃-C₁₂-cycloalkyl ring or aC₃-C₁₂-cycloalkenyl ring, which optionally can be substituted in one ormore places in the same way or differently with hydroxy, halogen, amino,C₁₋₆-alkoxy, or with the group —NHC₁₋₆-alkyl or —N-di-C₁₋₆-alkyl,

[0057] R⁶ and R⁷ are the same or different and stand for hydrogen,linear or branched C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkinyl, whichoptionally can be substituted in one or more places in the same way ordifferently with hydroxy, halogen, amino, C₁₋₆-alkoxy, or with the group—NHC₁₋₆-alkyl or —N-di-C₁₋₆-alkyl, or together form a C₃-C₁₂-cycloalkylring or a C₃-C₁₂-cycloalkenyl ring, which optionally can be substitutedin one or more places in the same way or differently with hydroxy,halogen, amino, C₁₋₆-alkoxy, or with the group —NHC₁₋₆-alkyl or—N-di-C₁₋₆-alkyl, or

[0058] R⁵ and R⁶ optionally together form a double bond,

[0059] T stands for —CH₂—, —O—, —CH₂═CH₂—, —CH≡CH—, —CH₂—O—CH₂—,—CH₂—O—, —O—CH₂— or ═CO, and

[0060] n stands for 0-6, as well as tautomers, isomers and saltsthereof,

[0061] have proven quite especially valuable.

[0062] Those compounds of general formula I, in which

[0063] R¹ stands for linear or branched C₁-C₆-alkyl, C₂-C₆-alkenyl,C₂-C₆-alkinyl, C₁-C₆-alkoxy, C₁-C₆-alkylthio or cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl,cyclodecyl, norbornyl, adamantanyl, cyclobutenyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl or cyclodecenyl,oxiranyl, oxethanyl, aziridinyl, azetidinyl, tetrahydrofuranyl,pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, dioxanyl,piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl,trithianyl, quinuclidinyl, pyrrolinyl, imidazolinyl, pyrazolinyl,pyranyl, thiinyl, dihydroazetyl, cyclopropenyl, cyclopentadienyl,phenyl, tropyl, cyclooctadienyl, indenyl, naphthyl, biphenyl, azulenyl,fluorenyl, anthracenyl, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, benzofuranyl, benzothienyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, oxepinyl, azocinyl, indolizinyl,indolyl, isoindolyl, indazolyl, benzimidazolyl, purinyl, quinolinyl,isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl,phenothiazinyl, 1,3-benzodioxol-5-yl, phenoxazinyl or xanthenyl, whichoptionally can be substituted in one or more places in the same way ordifferently with hydroxy, halogen, amino, C₁₋₆-alkyl, C₁₋₆-alkoxy,C₁₋₆-alkylthio, halo-C₁₋₆-alkyl, halo-C₁₋₆-alkoxy, C₁₋₆-alkoxycarbonyl,cyano, nitro, C₁₋₆-alkylsulfanyl, C₁₋₆-alkylsulfinyl,C₁₋₆-alkylsulfonyl, or can be substituted with the group—C(O)C₁₋₆-alkyl, —NHC₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, —CONH₂,—CONHC₁₋₆-alkyl or —CON-di-C₁₋₆-alkyl, or can be substituted withanother aryl or heteroaryl radical, which optionally itself can besubstituted in one or more places in the same way or differently withhydroxy, halogen, amino, C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio,halo-C₁₋₆-alkyl, halo-C₁₋₆-alkoxy, C₁₋₆-alkoxycarbonyl, cyano, nitro,C₁₋₆-alkylcarbonyl, C₁₋₆-alkylsulfanyl, C₁₋₆-alkylsulfinyl,C₁₋₆-alkylsulfonyl, or with the group —C(O)C₁₋₆-alkyl, —NHC₁₋₆-alkyl,—N-di-C₁₋₆-alkyl, —CONH₂, —CONHC₁₋₆-alkyl or —CON-di-C₁₋₆-alkyl,

[0064] R² and R³ are the same or different and stand for hydrogen,linear or branched C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl orC₁-C₆-alkoxy, which optionally can be substituted in one or more placesin the same way or differently with hydroxy, halogen, amino,C₁₋₆-alkoxy, or with the group —NHC₁₋₆-alkyl or —N-di-C₁₋₆-alkyl,

[0065] R⁴ and R⁵ are the same or different and stand for hydrogen,halogen, linear or branched C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl orC₁-C₆-alkoxy, which optionally can be substituted in one or more placesin the same way or differently with hydroxy, halogen, amino,C₁₋₆-alkoxy, or with the group —NHC₁₋₆-alkyl or —N-di-C₁₋₆-alkyl, ortogether stand for a carbonyl group, or together form a cyclic five- orsix-ring-acetal of the structure

[0066]  or

[0067] R² and R⁴ together form a C₃-C₇-cycloalkyl ring or aC₃-C₇-cycloalkenyl ring, which optionally can be substituted in one ormore places in the same way or differently with hydroxy, halogen, amino,C₁₋₆-alkoxy, or with the group —NHC₁₋₆-alkyl or —N-di-C₁₋₆-alkyl, or

[0068] R³ and R⁵ together form a C₃-C₇-cycloalkyl ring or aC₃-C₇-cycloalkenyl ring, which optionally can be substituted in one ormore places in the same way of differently with hydroxy, halogen, amino,C₁₋₆-alkoxy, or with the group —NHC₁₋₆-alkyl or —N-di-C₁₋₆-alkyl,

[0069] R⁶ and R⁷ are the same or different and stand for hydrogen,linear or branched C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkinyl, whichoptionally can be substituted in one or more places in the same way ordifferently with hydroxy, halogen, amino, C₁₋₆-alkoxy, or with the group—NHC₁₋₆-alkyl or —N-di-C₁₋₆-alkyl, or together form a C₃-C₇-cycloalkylring or a C₃-C₇-cycloalkenyl ring, which optionally can be substitutedin one or more places in the same way or differently with hydroxy,halogen, amino, C₁₋₆-alkoxy, or with the group —NHC₁₋₆-alkyl or—N-di-C₁₋₆-alkyl, or

[0070] R⁵ and R⁶ optionally together form a double bond,

[0071] T stands for —CH₂—, —O—, —CH₂═CH₂—, —CH≡CH—, —CH₂—O—CH₂—,—CH₂—O—, —O—CH₂— or ═CO, and

[0072] n stands for 0-6, as well as tautomers, isomers and saltsthereof,

[0073] are especially valuable.

[0074] Selected compounds are those compounds of general formula I, inwhich

[0075] R¹ stands for C₁-C₆-alkylthio, phenyl, biphenyl, thienyl,cyclopropyl, cyclohexyl, pyridyl, naphthyl, 1,3-benzodioxol-5-yl orisoxazolyl, which optionally can be substituted in one or more places inthe same way or differently with halogen, amino, cyano,C₁₋₆-alkyl-sulfonyl, C₁₋₆-alkyl, halo-C₁₋₆-alkyl, C₁₋₆-alkoxy,C₁₋₆-alkylthio, or with the group —C(O)C₁₋₆-alkyl, or which can besubstituted with phenyl, thienyl, naphthyl, pyridyl, furanyl orpyrimidinyl, which optionally itself can be substituted in one or moreplaces in the same way or differently with C₁₋₆-alkyl, C₁₋₆-alkoxy,amino, C₁₋₆-alkylsulfonyl, cyano or with the group —C(O)NH₂,

[0076] R¹, R³, R⁴, R⁵, R⁶ and R⁷ stand for hydrogen or C₁₋₆-alkyl,

[0077] T stands for the group —CH₂—, —CH₂—O—CH₂— or —CH₂—O—, and

[0078] n stands for 0-2, as well as tautomers, isomers and saltsthereof.

[0079] The production of the compounds of general formula I according tothe invention is preferably carried out by

[0080] a) a 1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl-amine of generalformula II

[0081] in which R², R³, R⁴, R⁵, R⁶ and R⁷ have the meanings that areindicated in general formula I,

[0082] being reacted with a compound of general formula III

R¹—COX  (III),

[0083] in which R¹ has the meaning that is indicated in general formulaI, and X stands for hydroxy, fluorine, chlorine, bromine or a leavinggroup,

[0084] to form compounds of general formulas IVa and IVb

[0085] in which R¹ has the meaning that is indicated in general formulaI, which then are hydrolyzed selectively under basic conditions to formthe compounds of general formula I,

[0086] or

[0087] b) a 1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl-amine of generalformula II

[0088] in which R², R³, R⁴, R⁵, R⁶ and R⁷ have the meanings that areindicated in general formula I,

[0089] being reacted with a compound of general formula V

R¹—CO—CCl₃  (V),

[0090] in which R¹ has the meaning that is indicated in general formulaI, to form a compound of general formula I,

[0091] or

[0092] c) if R¹ stands for a 4-halophenylacetyl radical in the meaningof general formula I, a compound of general formulas VI or VIa

[0093] in which R², R³, R⁴, R⁵, R⁶ and R⁷ have the meanings that areindicated in general formula I,

[0094] stands for a solid phase and Y stands for bromine or iodine,being reacted under the conditions of a Suzuki reaction with a boronicacid of general formula VII

[0095] in which R⁸ stands for aryl or heteroaryl, to form a compound ofgeneral formula Ia or Ib,

[0096] in which R², R³, R⁴, R⁵, R⁶ and R⁷ have the meanings that areindicated in general formula I, R⁸ stands for aryl or heteroaryl, and

[0097] means a solid phase, whereby in the case of the compound that isbonded to a solid phase, the cleavage is carried out by acid hydrolysis,

[0098] or

[0099] d) a compound of general formula VI or VIa, in which R¹ standsfor a 4-halophenylacetyl radical,

[0100] in which R², R³, R⁴, R⁵, R⁶ and R⁷ have the meanings that areindicated in general formula I,

[0101] means a solid phase, and Y stands for bromine or iodine, beingreacted under the conditions of a Miyaura reaction with a diboronic acidderivative of general formula VIII

[0102] to form compounds of general formulas IX or IXa

[0103] in which R², R³, R⁴, R⁵, R⁶ and R⁷ have the meanings that areindicated in general formula I, and

[0104] means a solid phase, and then the compounds of general formulasIX and IXa being reacted with a compound of general formula X,

R⁹Z  (X),

[0105] in which R⁹ stands for aryl or heteroaryl and Z stands forbromine or iodine, to form compounds of general formulas Ic or Id

[0106] in which R², R³, R⁴, R⁵, R⁶ and R⁷ have the meanings that areindicated in general formula I,

[0107] means a solid phase, and R⁹ stands for aryl or heteroaryl, and inthe case of the compound that is bonded to a solid phase, the cleavageis carried out by acidic hydrolysis, or

[0108] e) a compound of general formula XI

[0109] in which R¹ has the meanings that are indicated in generalformula I, being reacted with N-(1-cyclopenten-1-yl)-morpholine ofgeneral formula XII

[0110] to form compounds of general formula XIII

[0111] in which R¹ has the meanings that are indicated in generalformula I, and then the compounds of general formula XIII being cyclizedwith hydrazine to compounds of formula I,

[0112] or

[0113] f) a compound of general formula XIV,

[0114] in which X stands for oxygen or sulfur, being reacted with acompound of general formula XV in the presence of strong bases (e.g.,lithium diisopropylamide),

R¹—COOR¹⁰  (XV),

[0115] in which R¹ has the meaning that is indicated in general formulaI, and R¹⁰ stands for C₁-C₆-alkyl, to form a compound of general formulaI.

[0116] Process Variant a)

[0117] The reaction of 1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl-amineof formula II with a compound of formula III can be carried out in thepresence of a base such as triethylamine, N-methylmorpholine,N,N-diisopropylethylamine or pyridine in a suitable solvent, such astoluene, dichloromethane, chloroform, diethyl ether, tetrahydrofuran,acetonitrile, dioxane or N,N-dimethylformamide at a temperature ofbetween 0° C. and the boiling point of the solvent. One of the methods,known from peptide chemistry, for forming amides can also be used.

[0118] The reaction of a compound of general formula IVa and IVb to forma compound of formula I can be carried out in the presence of a basesuch as sodium hydroxide, potassium hydroxide, sodium carbonate,potassium carbonate or sodium methylate in a suitable solvent, such asmethanol, ethanol or a mixture that consists of methanol or ethanol withwater at room temperature.

[0119] Process Variant b)

[0120] The reaction of 1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl-amineof formula II with a compound of formula V to form a compound of formulaI can be carried out in the presence of a base such as triethylamine,N-methylmorpholine, N,N-diisopropyl ethylamine in a suitable solvent,such as tetrahydrofuran, acetonitrile, dioxane or N,N-dimethylformamideat a temperature of between room temperature and the boiling point ofthe solvent.

[0121] Process Variant c)

[0122] The Suzuki reaction of a compound of formula VI with a boronicacid of formula VII can be carried out in the presence of a base such ascesium fluoride, sodium carbonate or potassium carbonate and a catalystsuch as Pd(PPh₃)₄, PdCl₂(PPh₃)₂, or Pd(OAc)₂/PPh₃ in a suitable solventsuch as dioxane, tetrahydrofuran, dimethoxyethane or a mixture thatconsists of methanol and dimethoxyethane at a temperature of betweenroom temperature and the boiling point of the solvent.

[0123] Process Variant d)

[0124] The Miyaura reaction of a compound of formula VI with a diboronicacid derivative of formula VIII to form a compound of formula IX can becarried out in the presence of a base, such as potassium acetate ortriethylamine and a catalyst such as PdCl₂(diphenylphosphinoferrocene)or PdCl₂(PPh₃)₂ in a suitable solvent such as acetonitrile, dioxane,dimethoxyethane, dimethyl sulfoxide or N,N-dimethylformamide at atemperature of between room temperature and the boiling point of thesolvent.

[0125] The reaction of a compound of formula IX with a compound offormula X can be carried out in the presence of a base such as sodiumcarbonate, potassium carbonate or potassium phosphate and a catalystsuch as Pd(PPh₃)₄ or PdCl₂(PPh₃)₂ in a suitable solvent such as dioxane,tetrahydrofuran, dimethoxyethane or N,N-dimethylformamide at atemperature of between room temperature and the boiling point of thesolvent.

[0126] Process Variant e)

[0127] The reaction of a compound of formula XI withN-(1-cyclopenten-1-yl)-morpholine of formula XII to form a compound offormula XIII can be carried out in a suitable solvent such as petroleumether, ligroin, cyclohexane, hexane, pentane, acetonitrile ordichloromethane at a temperature of between room temperature and theboiling point of the solvent.

[0128] The reaction of a compound of formula XIII with hydrazine orhydrazine hydrate can be carried out in a suitable solvent such asmethanol, ethanol or tetrahydrofuran at a temperature of between roomtemperature and the boiling point of the solvent.

[0129] Process Variant f)

[0130] The reaction of a compound of formula XIV with a compound offormula XV to form a compound of formula I can be carried outanalogously to what is described in J. Heterocyclic Chem. 34, 1549(1997).

[0131] The 1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl-amine of formula IIis new and can be obtained according to the methods that are describedin the literature, e.g., from cyclopentanone thiosemicarbazone (J.Heterocyclic Chem. 34, 1549 (1997)) or fromcyclopentanone-2-carbonitrile (J. Org. Chem., 52, 5538 (1987)).

[0132] Subjects of this invention are thus also compounds of generalformula II,

[0133] in which R², R³, R⁴, R⁵, R⁶ and R⁷ have the meanings that areindicated in general formula I, as valuable intermediate products forthe production of the compounds of general formula I according to theinvention.

[0134] The compounds of formulas III, V, VII, VIII, X, XI, XII, XIV andXV are either commercially available or can be produced according tomethods that are known in the literature.

[0135] The compounds of formula I and the precursors for theirproduction that are bonded to the solid phase can be produced accordingto methods that are known in the art. Also, the cleavage can beperformed by acid hydrolysis to form the free compounds according to theknown methods.

[0136] The compounds according to the invention essentially inhibitcyclin-dependent kinases, upon which their action is based, for example,against cancer, such as solid tumors and leukemia; auto-immune diseases,such as psoriasis, alopecia and multiple sclerosis; chemotherapyagent-induced alopecia and mucositis; cardiovascular diseases, such asstenoses, arterioscleroses and restenoses; infectious diseases, such as,e.g., those caused by unicellular parasites, such as trypanosoma,toxoplasma or plasmodium, or those caused by fungi; nephrologicaldiseases, such as, e.g., glomerulonephritis; chronic neurodegenerativediseases, such as Huntington's disease, amyotrophic lateral sclerosis,Parkinson's disease, AIDS dementia and Alzheimer's disease; acuteneurodegenerative diseases, such as ischemias of the brain andneurotraumas; viral infections, such as, e.g., cytomegalic infections,herpes, Hepatitis B and C, and HIV diseases.

[0137] This invention thus also relates to the use of compoundsaccording to the invention in these indications.

[0138] The eukaryotic cell-division cycle ensures the duplication of thegenome and its dispersion to the daughter cells by passing through acoordinated and regulated sequence of events. The cell cycle is dividedinto four successive phases: The G1 phase represents the time before theDNA replication in which the cell grows and is sensitive to externalstimuli. In the S phase, the cell replicates its DNA, and in the G2phase, preparations are made for entry into mitosis. In the mitosis (Mphase), the replicated DNA is separated, and the cell division iscompleted.

[0139] The cyclin-dependent kinases (CDKs), a family of Ser/Thr-kinases,whose members require the binding of a cyclin (Cyc) as a regulatorysubunit in order for them to activate, drive the cell through the cellcycle. Different CDK/Cyc pairs are active in the various phases of thecell cycle. CDK/Cyc pairs that are important to the basic function ofthe cell cycle are, for example, CDK4(6)/CycD, CDK2/CycE, CDK2/CycA,CDK1/CycA and CDK1/CycB. Some members of the CDK enzyme family have aregulatory function by influencing the activity of the above-mentionedcell cycle CDKs, while no specific function could be associated withother members of the CDK enzyme family. One of the latter, CDK5, isdistinguished in that it has an a typical regulatory subunit (p35) thatdeviates from the cyclins, and its activity is highest in the brain.

[0140] The entry into the cell cycle and the passage through the“restriction points,” which marks the independence of a cell fromfurther growth signals for the completion of the cell division that hasbegun, are controlled by the activity of the CDK4(6)/CycD and CDK2/CycEcomplexes. The essential substrate of these CDK complexes is theretinoblastoma protein (Rb), the product of the retinoblastoma tumorsuppressor gene. Rb is a transcriptional co-repressor protein. Inaddition to other, still largely little understood mechanisms, Rb bindsand inactivates transcription factors of the E2F type and formstranscriptional repressor complexes with histone-deacetylases (HDAC)(Zhang, H. S. et al. (2000). Exit from G1 and S Phase of the Cell Cycleis Regulated by Repressor Complexes Containing HDAC-Rb-hSWI/SNF andRb-hSWI/SNF. Cell 101, 79-89). By the phosphorylation of Rb by CDKs,bonded E2F transcription factors are released and result intranscriptional activation of genes, whose products are required for theDNA synthesis and the progression through the S-phase. In addition, theRb-phosphorylation brings about the breakdown of the Rb-HDAC complexes,by which additional genes are activated. The phosphorylation of Rb byCDK's is to be treated as equivalent to exceeding the “restrictionpoints.” For the progression through the S-phase and its completion, theactivity of the CDK2/CycE and CDK2/CycA complexes is necessary, e.g.,the activity of the transcription factors of the E2F type is turned offby means of phosphorylation by CDK2/CycA as soon as the cells areentered into the S-phase. After replication of DNA is complete, the CDK1in the complex with CycA or CycB controls the entry into and the passagethrough phases G2 and M (FIG. 1).

[0141] According to the extraordinary importance of the cell-divisioncycle, the passage through the cycle is strictly regulated andcontrolled. The enzymes that are necessary for the progression throughthe cycle must be activated at the correct time and are also turned offagain as soon as the corresponding phase is passed. Correspondingcontrol points (“checkpoints”) stop the progression through the cellcycle if DNA damage is detected, or the DNA replication or the creationof the spindle device is not yet completed.

[0142] The activity of the CDKs is controlled directly by variousmechanisms, such as synthesis and degradation of cyclins, complexing ofthe CDKs with the corresponding cyclins, phosphorylation anddephosphorylation of regulatory Thr and Tyr radicals, and the binding ofnatural inhibitory proteins. While the amount of protein of the CDKs ina proliferating cell is relatively constant, the amount of theindividual cyclins oscillates with the passage through the cycle. Thus,for example, the expression of CycD during the early G1 phase isstimulated by growth factors, and the expression of CycE is inducedafter the “restriction points” are exceeded by the activation of thetranscription factors of the E2F type. The cyclins themselves aredegraded by the ubiquitin-mediated proteolysis. Activating andinactivating phosphorylations regulate the activities of the CDKs, forexample phosphorylate CDK-activating kinases (CAKs) Thr160/161 of theCDK1, while, by contrast, the families of Wee1/Myt1 inactivate kinasesCDK1 by phosphorylation of Thr14 and Tyr15. These inactivatingphosphorylations can be destroyed in turn by cdc25 phosphatases. Theregulation of the activity of the CDK/Cyc complexes by two families ofnatural CDK inhibitor proteins (CKIs), the protein products of the p21gene family (p21, p27, p57) and the p16 gene family (p15, p16, p18, p19)is very significant. Members of the p21 family bind to cyclin complexesof CDKs 1,2,4,6, but inhibit only the complexes that contain CDK1 orCDK2. Members of the p16 family are specific inhibitors of the CDK4 andCDK6 complexes.

[0143] The plane of control point regulation lies above this complexdirect regulation of the activity of the CDKs. Control points allow thecell to track the orderly sequence of the individual phases during thecell cycle. The most important control points lie at the transition fromG1 to S and from G2 to M. The G1 control point ensures that the celldoes not initiate any DNA synthesis unless it has proper nutrition,interacts correctly with other cells or the substrate, and its DNA isintact. The G2/M control point ensures the complete replication of DNAand the creation of the mitotic spindle before the cell enters intomitosis. The G1 control point is activated by the gene product of thep53 tumor suppressor gene. p53 is activated after detection of changesin metabolism or the genomic integrity of the cell and can triggereither a stopping of the cell cycle progression or apoptosis. In thiscase, the transcriptional activation of the expression of the CDKinhibitor protein p21 by p53 plays a decisive role. A second branch ofthe G1 control point comprises the activation of the ATM and Chk1kinases after DNA damage by UV light or ionizing radiation and finallythe phosphorylation and the subsequent proteolytic degradation of thecdc25A phosphatase (Mailand, N. et al. (2000). Rapid Destruction ofHuman cdc25A in Response to DNA Damage. Science 288, 1425-1429). Ashutdown of the cell cycle results from this, since the inhibitoryphosphorylation of the CDKs is not removed. After the G2/M control pointis activated by damage of the DNA, both mechanisms are involved in asimilar way in stopping the progression through the cell cycle.

[0144] The loss of the regulation of the cell cycle and the loss offunction of the control points are characteristics of tumor cells. TheCDK-Rb signal path is affected by mutations in over 90% of human tumorcells. These mutations, which finally result in inactivatingphosphorylation of the RB, include the over-expression of D- andE-cyclins by gene amplification or chromosomal translocations,inactivating mutations or deletions of CDK inhibitors of the p16 type,as well as increased (p27) or reduced (CycD) protein degradation. Thesecond group of genes, which are affected by mutations in tumor cells,codes for components of the control points. Thus p53, which is essentialfor the G1 and G2/M control points, is the most frequently mutated genein human tumors (about 50%). In tumor cells that express p53 withoutmutation, it is often inactivated because of a greatly increased proteindegradation. In a similar way, the genes of other proteins that arenecessary for the function of the control points are affected bymutations, for example ATM (inactivating mutations) or cdc25phosphatases (over-expression).

[0145] Convincing experimental data indicate that CDK2/Cyc complexesoccupy a decisive position during the cell cycle progression: (1) Bothdominant-negative forms of CDK2, such as the transcriptional repressionof the CDK2 expression by anti-sense oligonucleotides, produce astopping of the cell cycle progression. (2) The inactivation of the CycAgene in mice is lethal. (3) The disruption of the function of theCDK2/CycA complex in cells by means of cell-permeable peptides resultedin tumor cell-selective apoptosis (Chen, Y. N. P. et al. (1999).Selective Killing of Transformed Cells by Cyclin/Cyclin-Dependent Kinase2 Antagonists. Proc. Natl. Acad. Sci. USA 96, 4325-4329).

[0146] Changes of the cell cycle control play a role not only incarcinoses. The cell cycle is activated by a number of viruses, both bytransforming viruses as well as by non-transforming viruses, to makepossible the reproduction of viruses in the host cell. The false entryinto the cell cycle of normally post-mitotic cells is associated withvarious neurodegenerative diseases. The mechanisms of the cell cycleregulation, their changes in diseases and a number of approaches todevelop inhibitors of the cell cycle progression and especially the CDKswere already described in a detailed summary in several publications(Sielecki, T. M. et al. (2000). Cyclin-Dependent Kinase Inhibitors:Useful Targets in Cell Cycle Regulation. J. Med. Chem. 43, 1-18; Fry, D.W. & Garrett, M. D. (2000). Inhibitors of Cyclin-Dependent Kinases asTherapeutic Agents for the Treatment of Cancer. Curr. Opin. Oncol. Endo.Metab. Invest. Drugs 2, 40-59; Rosiania, G. R. & Chang, Y. T. (2000).Targeting Hyperproliferative Disorders with Cyclin-Dependent KinaseInhibitors. Exp. Opin. Ther. Patents 10, 215-230; Meijer L. et al.(1999). Properties and Potential Applications of Chemical Inhibitors ofCyclin-Dependent Kinases. Pharmacol. Ther. 82, 279-284; Senderowicz, A.M. & Sausville, E. A. (2000). Preclinical and Clinical Development ofCyclin-Dependent Kinase Modulators. J. Natl. Cancer Inst. 92, 376-387).

[0147] To use the compounds according to the invention as pharmaceuticalagents, the latter are brought into the form of a pharmaceuticalpreparation, which in addition to the active ingredient for enteral orparenteral administration contains suitable pharmaceutical, organic orinorganic inert support media, such as, for example, water, gelatin, gumarabic, lactose, starch, magnesium stearate, talc, vegetable oils,polyalkylene glycols, etc. The pharmaceutical preparations can bepresent in solid form, for example as tablets, coated tablets,suppositories, or capsules, or in liquid form, for example as solutions,suspensions, or emulsions. Moreover, they optionally contain adjuvants,such as preservatives, stabilizers, wetting agents or emulsifiers; saltsfor changing the osmotic pressure or buffers.

[0148] These pharmaceutical preparations are also subjects of thisinvention.

[0149] For parenteral administration, especially injection solutions orsuspensions, especially aqueous solutions of active compounds inpolyhydroxyethoxylated castor oil, are suitable.

[0150] As carrier systems, surface-active adjuvants such as salts ofbile acids or animal or plant phospholipids, but also mixtures thereofas well as liposomes or their components, can also be used.

[0151] For oral administration, especially tablets, coated tablets orcapsules with talc and/or hydrocarbon vehicles or binders, such as, forexample, lactose, corn or potato starch, are suitable. Theadministration can also be carried out in liquid form, such as, forexample, as a juice, to which optionally a sweetener is added.

[0152] Enteral, parenteral and oral administrations are also subjects ofthis invention.

[0153] The dosage of the active ingredients can vary depending on themethod of administration, age and weight of the patient, type andseverity of the disease to be treated and similar factors. The dailydose is 0.5-1000 mg, preferably 50-200 mg, whereby the dose can be givenas a single dose to be administered once or divided into two or moredaily doses.

[0154] Subjects of this invention also include the use of compounds ofgeneral formula I for the production of a pharmaceutical agent fortreating cancer, auto-immune diseases, cardiovascular diseases,chemotherapy agent-induced alopecia and mucositis, infectious diseases,nephrological diseases, chronic and acute neurodegenerative diseases andviral infections, whereby cancer is defined as solid tumors andleukemia; auto-immune diseases are defined as psoriasis, alopecia andmultiple sclerosis; cardiovascular diseases are defined as stenoses,arterioscleroses and restenoses; infectious diseases are defined asdiseases that are caused by unicellular parasites; nephrologicaldiseases are defined as glomerulonephritis; chronic neurodegenerativediseases are defined as Huntington's disease, amyotrophic lateralsclerosis, Parkinson's disease, AIDS dementia and Alzheimer's disease;acute neurodegenerative diseases are defined as ischemias of the brainand neurotraumas; and viral infections are defined as cytomegalicinfections, herpes, Hepatitis B or C, and HIV diseases.

[0155] Subjects of this invention also include pharmaceutical agents fortreating the above-cited diseases, which contain at least one compoundaccording to general formula I, as well as pharmaceutical agents withsuitable formulation substances and vehicles.

[0156] The compounds of general formula I according to the inventionare, i.a., excellent inhibitors of the cyclin-dependent kinases, such asCDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9, as well as theglycogen-synthase-kinase (GSK-3β).

[0157] The following examples explain the production of the compoundsaccording to the invention, without limiting the invention to theseexamples.

EXAMPLE 1.0

[0158]2-(3′-Fluoro-biphenyl-4-yl)-N-(1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl)-acetamide

[0159] 230 mg of 2-(3′-fluoro-biphenyl-4-yl)-acetic acid is dissolved in5 ml of tetrahydrofuran, mixed with 0.1 ml of oxalyl chloride and onedrop of dimethylformamide, and stirred for 2 hours at room temperature.62 mg of 1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl-amine is added tothis solution. The mixture is stirred for 12 hours at room temperatureand then concentrated by evaporation. The residue is extracted withethyl acetate. The extract is washed with sodium bicarbonate solutionand water, dried on magnesium sulfate and concentrated by evaporation.The brown residue is dissolved in 5 ml of methanol and mixed with 0.1 mlof a 30% sodium methylate solution. It is stirred for 4 hours at roomtemperature and then concentrated by evaporation. The residue isextracted with ethyl acetate. The extract is washed with sodiumbicarbonate solution and sodium chloride solution, dried on magnesiumsulfate and concentrated by evaporation. A yellow, resinous oil isobtained that is purified by HPLC.2-(3′-Fluoro-biphenyl-4-yl)-N-(1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl)-acetamidewith a melting point of 180-181° C. is obtained.

[0160] Production of the Starting Material

[0161] 1,4,5,6-Tetrahydro-cyclopentapyrazol-3-yl-amine

[0162] 5.3 g of cyclopentanone thiosemicarbazone is carefully added at0° C. to a solution of lithium diisopropylamine in 200 ml oftetrahydrofuran (from 29 ml of diisopropylamine and 81 ml of 1.6 Mn-butyllithium), whereby the temperature rises to 30° C. Then, it isstirred for 2 hours at room temperature. Then, 150 ml of 4N hydrochloricacid is carefully added in drops (exothermic, H₂S development), and themixture is refluxed for 30 minutes. Then, it is cooled to 5° C. and setat pH 14 with sodium hydroxide solution. The aqueous phase is extractedthree times with tetrahydrofuran/ethyl acetate 95:5. The crude productis purified by column chromatography on silica gel with 1 l of ethylacetate and 1 1 of ethyl acetate/methanol 9:1 with the addition of 3%triethylamine. 2.58 g of 1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl-aminewith a melting point of 116-120° C. is obtained.

EXAMPLE 1.1

[0163]2-(Biphenyl-4-yl)-N-[6-methyl-(1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl)]-acetamide

[0164] The production of2-(biphenyl-4-yl)-N-[6-methyl-(1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl)]-acetamideis carried out analogously to Example 1.0.

[0165] Production of the Starting Material

[0166] 6-Methyl-1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl-amine

[0167] A mixture that consists of 1-methylcyclopentanone (9.82 g, 100mmol) and dimethylformamide-dimethylacetal (26 ml, 150 mmol) is heatedfor 4.5 hours at 110° C., concentrated by evaporation and distilled in aball-tube furnace at 160-170° C./2 mbar.

[0168] Yield: 7.7 g

[0169] MS-CI (NH3): 154

[0170] A solution of enamine (7.65 g, 50 mmol) in methanol (50 ml) ismixed with hydroxylamine-hydrochloride (3.47 g, 50 mmol), stirred for 1hour at 50° C., mixed with diethyl ether, suctioned off, and the motherliquor is concentrated by evaporation.

[0171] Yield: 6.08 g isoxazole.

[0172] MS-EI: 124

[0173] A solution of isoxazole (6.1 g, 50 mmol) in diethyl ether (100ml) is mixed drop by drop with 0.5 M sodium methylate solution inmethanol (100 ml, 50 mmol), and it is stirred for 24 hours at 23° C. Thesolution is concentrated by evaporation, the residue is cooled, mixedcarefully with cold water, stirred with diethyl ether, and the organicphase is separated. The alkaline water phase is brought to pH 1 with 6Nhydrochloric acid (12 ml), extracted with diethyl ether (4×40 ml), theorganic phase is dried (Na₂SO₄), filtered off and concentrated byevaporation.

[0174] Yield: 4.6 g of 2-cyano-5-methylcyclopentanone.

[0175] MS-CI (NH3): 141

[0176] IR: 2240 cm−1 (CN), 1760 cm−1 (CO)

[0177] A solution of 2-cyano-5-methylcyclopentanone (1.23 g, 10 mmol) inethanol (20 ml) is mixed at 23° C. with hydrazine hydrate (80% in water,0.68 g, 10.8 mmol), and it is stirred for 2.5 hours at 23° C. 4NHCl-dioxane solution (2.5 ml, 10 mmol) is added into this solution, itis stirred for 1.5 hours at 23° C., concentrated by evaporation to halfthe volume, and the precipitated hydrochloride is suctioned off. Themother liquor is concentrated by evaporation, the residue is stirred indiethyl ether/ethanol, suctioned off and dried.

[0178] Yield: 780 mg of6-methyl-1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl-amine hydrochloride.

[0179] Melting point 191° C. (decomposition)

[0180] MS-CI (NH3): 138

[0181] 1H-NMR (d6-DMSO): 13.6 (br.s, NH), 6.9 (br.s, NH2), 3.1 (sext.,J≈7 Hz, 1H), 2.7-2.3 (m, 3H), 2.0-1.9 (m, 1H), 1.18 (d, J=6.7, 3H).

[0182] Similarly produced are also the following compounds:

R², R³, R⁴, R⁵, R⁶ and R⁷ = hydrogen T = —CH₂— R¹ ⁼

Example Melting Point No. n R^(i) R^(ii) R^(iii) R^(iv) R^(v) MW [° C.]1.2 1 H H F H H 335.3802 161-163 1.3 1 H H H H F 335.3802 179-181 1.4 1H H H H —OCH₃ 347.4159 150 1.5 1 H H H —OCH₃ H 347.4159 110-114 1.6 1 HH —OCH₃ H H 347.4159 168-172 1.7 1 H H H —C(O)CH₃ H 359.4269 150 1.8 1 HH —C(O)CH₃ H H 359.4269 112-114 1.9 1 H H H H H 317.39 NMR (CDCl₃): m2.42 (2H), t 2.68 (4H), s 3.71 (2H), d 7.34 (4H), t 7.42 (1H), d 7.57(4H), sbr 8.36 (1H) 1.10 1 H H CN H H 342.40 210 (dec.) 1.11 1 H H H NH₂H 1.12 1 H H —SO₂CH₃ H H

[0183]

R², R³, R⁴, R⁵, R⁶ and R⁷ = hydrogen T = —CH₂— R¹ =

Melting Point [° C.] Example No. X Y Q n MW MS/NMR 2.0 H H H 1 247.3207248 (100%, M + H); 150 (12%); 123 (24%) 2.1 H H H 0 233.2939 234 (100%,M + H); 204 (36%); 188 (12%); 124 (3%)

[0184]

R², R³, R⁴, R⁵, R⁶ and R⁷ = hydrogen T = —CH₂— R¹ =

Melting Point [° C.] Example No. X Y n MW MS/NMR 3.0 H Ph 0 267.3303 268(100%, M + H); 204 (43%); 188 (24%); 123 (11%) 3.1 H H 0 191.2327 192(100%, M + H)

[0185]

R², R³, R⁴, R⁵, R⁶ and R⁷ = hydrogen T = —CH₂— R¹ =

Melting Example Point [° C.] No. X Y n Z M Q MW MS/NMR 4.0 H H 0 H H H233.3131 234 (100%, M + H); 150 (3%); 123 (28%)

[0186]

R², R³, R⁴, R⁵, R⁶ and R⁷ = hydrogen T = —CH₂— Melting Example Point [°C.] No. n R¹ MW MS/NMR 5.0 2 —SCH₃ 225.3145 226 (100%, M + H); 204 (6%);188 (3%); 150 (5%); 123 (22%) 5.1 0

271.2747 272 (100%, M + H); 204 (8%); 188 (5%); 149 (46%) 5.2 0

228.2538 5.3 1

291.3523 176-178 5.4 0

228.2538

[0187]

R², R³, R⁴, R⁵, R⁶ and R⁷ = hydrogen T = —CH₂— R¹ =

Ex- Melting ample Point [° C.] No. N m R^(i) R^(ii) R^(iii) R^(iv) R^(v)MW MS/NMR 6.0 1 1 H H H H H 271.3183 272 (100%, M + H); 150 (3%); 123(5%) 6.1 1 0 —CH₃ H Cl H H 305.7634 306 (100%, M + H); 150 (11%); 123(21%)

[0188]

R², R³, R⁴, R⁵, R⁶ and R⁷ = hydrogen R¹ =

Melting Point Example [° C.] No. N R^(x) R^(y) MW MS/NMR 7.0 0 Ph —CH₃308.3394 309 (100%, M + H); 204 (28%); 188 (9%); 144 (15%); 124 (7%)

[0189]

R², R³, R⁴, R⁵, R⁶ and R⁷ = hydrogen T = —CH₂—

Example Melting Point [° C.] No. X Y n Z M Q MW MS/NMR 8.0 —OCH₃ —OCH₃ 1H H H 301.3441 302 (100%, M + H); 151 (22%; 123 (12%) 8.1 H F 1 H H H259.2826 260 (100%, M + H); 204 (25%); 188 (18%); 150 (11%); 123 (34%)8.2 —OCH₃ H 1 H H H 271.3183 272 (100%, M + H); 204 (7%); 124 (9%) 8.3 HH 2 H H H 255.3193 256 (100%), M + H); 204 (29%); 188 (21%); 150 (7%);123 (53%) 8.4 H —OCH₃ 1 H H H 271.3183 272 (100%, M + H); 148 (12%); 121(19%) 8.5 H H 1 H H H 241.2925 242 (100%, M + H); 150 (8%); 123 (30%)8.6 H H 0 H H H 227.2657 228 (100%, M + H); 204 (6%); 187 (8%) 8.7 —OCH₃H 1 H —OCH₃ H 301.3441 302 (100%), M + H 8.8 —CF₃ H 0 H H H 295.2628 296(100%, M + H); 204 (22%); 188 (12%) 8.9 F H 0 H H H 245.2558 246 (100%,M + H); 204 (22%); 188 (12%); 123 (25%) 8.10 H —OCH₃ 0 H H H 257.2915258 (100%, M + H); 204 (40%); 188 (15%) 8.11 H I 1 H H H 367.1846180-181 8.12

H 1 H H H 317.3901 180-181 8.13 Br H 1 H H H 320.1886 208-209 8.14 H Br1 H H H 320.1886 164-166 8.15 H —SCH₃ 1 H H H 287.3853 164-166 8.16 H—C(CH₃)₃ 1 H H H 297.40 NMR (CDCl₃): s 1.32 (9H), m 2.44 (2H), t 2.69(4H), s 3.70 (2H), d 7.22 (2H), d 7.40 (2H), sbr 7.81 (1H) 8.17 H Cl 1 HH H 275.7376 NMR (CDCl₃): m 2.43 (2H), t 2.68 (4H), s 3.61 (2H), d 7.20(2H), d 7.38 (2H), sbr 8.53 (1H) 8.18 H

0 H H H 200 (decomposition) 8.19 H

1 H H H 323.42 217-218 8.20 H

1 H H H 337.35 155-156 8.21 H

1 H H H 8.22 H

1 H H H 8.23 H

1 H H H 8.24 H

1 H H H 8.25 H

1 H H H 8.26

H 1 H H H 188 8.27

H 1 H H H 8.28

H 1 H H H 8.29

H 1 H H H 8.30

H 1 H H H 8.31

H 1 H H H 8.32

H 1 H H H 8.33

H 1 H H H 342.40 173 8.34

H 1 H H H 360.42 205 (dec.)

[0190]

R², R³, R⁴, R⁵, R⁶ and R⁷ = hydrogen T = —CH(CH₃)— R¹ =

Melting Point Example [° C.] No. N R^(i) R^(ii) R^(iii) R^(iv) R^(v) MWMS/NMR 9.0 1 H H H H H 349.41 218-220

[0191] The following examples describe the biological action of thecompounds according to the invention without limiting the invention tothese examples.

[0192] Sample Application 1

[0193] CDK2/CycE Kinase Assay

[0194] Recombinant CDK2- and CycE-GST-fusion proteins, purified frombaculovirus-infected insect cells (Sf9), were obtained by Dr. DieterMarmé, Klinik für Tumorbiologie [Clinic for Tumor Biology], Freiburg.Histone IIIS, which was used as a kinase substrate, was purchased by theSigma Company.

[0195] CDK2/CycE (50 ng/measuring point) was incubated for 15 minutes at22° C. in the presence of various concentrations of test substances (0μm, as well as within the range of 0.01-100 μm) in assay buffer [50 mmolof tris/HCl pH 8.0, 10 mmol of MgCl₂, 0.1 mmol of Na ortho-vanadate, 1.0mmol of dithiothreitol, 0.5 μm of adenosine triphosphate (ATP), 10μg/measuring point of histone IIIS, 0.2 μCi/measuring point of ³³P-gammaATP, 0.05% NP40, 12.5% dimethyl sulfoxide]. The reaction was stopped byadding EDTA solution (250 mmol, pH 8.0, 14 μl/measuring point).

[0196] From each reaction batch, 10 μl was applied to P30 filter strips(Wallac Company), and non-incorporated ³³P-ATP was removed by subjectingthe filter strips to three washing cycles for 10 minutes each in 0.5%phosphoric acid. After the filter strips were dried for one hour at 70°C., the filter strips were covered with scintillator strips (MeltiLex™A, Wallac Company) and baked for one hour at 90° C. The amount ofincorporated ³³P (substrate phosphorylation) was determined byscintillation measurement in a gamma-radiation measuring device(Wallac).

[0197] Sample Application 2

[0198] Proliferation Assay

[0199] Cultivated human MCF7 tumor cells were flattened out at a densityof 5000 cells/measuring point in a 96-well multititer plate in 200 μl ofthe corresponding growth medium. After 24 hours, the cells of one plate(zero-point plate) were colored with crystal violet (see below), whilethe medium of the other plates was replaced by fresh culture medium (200μl), to which the test substances were added in various concentrations(0 μm, as well as in the range of 0.01-30 μm; the final concentration ofthe solvent dimethyl sulfoxide was 0.5%). The cells were incubated for 4days in the presence of test substances. The cell proliferation wasdetermined by coloring the cells with crystal violet: the cells werefixed by adding 20 μl/measuring point of a 11% glutaric aldehydesolution for 15 minutes at room temperature. After three washing cyclesof the fixed cells with water, the plates were dried at roomtemperature. The cells were colored by adding 100 μl/measuring point ofa 0.1% crystal violet solution (pH was set at 3 by adding acetic acid).After three washing cycles of the colored cells with water, the plateswere dried at room temperature. The dye was dissolved by adding 100μl/measuring point of a 10% acetic acid solution. The extinction wasdetermined by photometry at a wavelength of 595 nm. The change of cellgrowth, in percent, was calculated by standardization of the measuredvalues to the extinction values of the zero-point plate (=0%) and theextinction of the untreated (0 μm) cells (=100%). CDK2/CycE Example No.IC₅₀ [μM] 1.0 7.0 1.2 <10.0 1.3 7.0 1.4 <10.0 1.5 <10.0 1.6 <10.0 1.74.3 1.8 6.5 1.9 1.0 2.0 4.0 2.1 4.0 3.1 4.0 5.1 4.0 8.1 3.0 8.2 7.6 8.33.0 8.4 0.7 8.5 1.5 8.6 7.0 8.7 5.2 8.9 5.0 8.10 6.0 8.11 0.8 8.12 8.08.13 1.5 8.14 1.1 8.15 1.5 8.16 1.0 8.17 1.5

1. Compounds of general formula I, in which

in which R¹ stands for linear or branched C₁-C₆-alkyl, C₂-C₆-alkenyl,C₂-C₆-alkinyl, C₁-C₆-alkoxy, C₁-C₆-alkylthio or C₃-C₁₂-cycloalkyl,C₃-C₁₂-cycloalkenyl, C₃-C₁₂-heterocycloalkyl, C₃-C₁₂-heterocycloalkenyl,aryl or heteroaryl, which optionally can be substituted in one or moreplaces in the same way or differently, R² and R³ are the same ordifferent and stand for hydrogen, linear or branched C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkinyl or C₁-C₆-alkoxy, which optionally can besubstituted in one or more places in the same way or differently, R⁴ andR⁵ are the same or different and stand for hydrogen, halogen, linear orbranched C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl or C₁-C₆-alkoxy,which optionally can be substituted in one or more places in the sameway or differently, or together stand for a carbonyl group, or togetherform a cyclic five- or six-ring-acetal with O,O; N,O; O,S; or S,S, whichoptionally can be substituted with C₁-C₆-alkyl, or R² and R⁴ togetherform a C₃-C₁₂-cycloalkyl ring or a C₃-C₁₂-cycloalkenyl ring, whichoptionally can be substituted in one or more places in the same way ordifferently, R⁶ and R⁷ are the same or different and stand for hydrogen,linear or branched C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₆-alkinyl, whichoptionally can be substituted in one or more places in the same way ordifferently, or together form a C₃-C₁₂-cycloalkyl ring or aC₃-C₁₂-cycloalkenyl ring, which optionally can be substituted in one ormore places in the same way or differently, or R⁵ and R⁶ optionallytogether form a double bond, or R³ und R⁵ together form aC₃-C₁₂-cycloalkyl ring or a C₃-C₁₂-cycloalkenyl ring, which optionallycan be substituted in one or more places in the same way or differently,T stands for —CH₂—, —O—, —CH₂═CH₂—, —CH≡CH—, —CH₂—O—CH₂—, —CH₂—O—,—O—CH₂— or ═CO, and n stands for 0-6, as well as tautomers, isomers andsalts thereof.
 2. Compounds of general formula I, according to claim 1,in which R¹ stands for linear or branched C₁-C₆-alkyl, C₂-C₆-alkenyl,C₂-C₆-alkinyl, C₁-C₆-alkoxy, C₁-C₆-alkylthio or C₃-C₁₂-cycloalkyl,C₃-C₁₂-cycloalkenyl, C₃-C₁₂-heterocycloalkyl, C₃-C₁₂-heterocycloalkenyl,aryl or heteroaryl, which optionally can be substituted in one or moreplaces in the same way or differently with hydroxy, halogen, amino,C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, halo-C₁₋₆-alkyl,halo-C₁₋₆-alkoxy, C₁₋₆-alkoxycarbonyl, cyano, nitro, C₁₋₆-alkylsulfanyl,C₁₋₆-alkylsulfinyl, C₁₋₆-alkylsulfonyl, or with the group—C(O)C₁₋₆-alkyl, —NHC₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, —CONH₂,—CONHC₁₋₆-alkyl or —CON-di-C₁₋₆-alkyl, or can be substituted withanother aryl radical or heteroaryl radical that optionally itself can besubstituted in one or more places in the same way or differently, R² andR³ are the same or different and stand for hydrogen, linear or branchedC₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl or C₁-C₆-alkoxy, whichoptionally can be substituted in one or more places in the same way ordifferently with hydroxy, halogen, amino, C₁₋₆-alkoxy, or with the group—NHC₁₋₆-alkyl or —N-di-C₁₋₆-alkyl, R⁴ and R⁵ are the same or differentand stand for hydrogen, halogen, linear or branched C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkinyl or C₁-C₆-alkoxy, which optionally can besubstituted in one or more places in the same way or differently withhydroxy, halogen, amino, C₁₋₆-alkoxy, or with the group —NHC₁₋₆-alkyl or—N-di-C₁₋₆-alkyl, or together stand for a carbonyl group, or togetherform a cyclic five- or six-ring-acetal of the structure

 or R² and R⁴ together form a C₃-C₁₂-cycloalkyl ring or aC₃-C₁₂-cycloalkenyl ring, which optionally can be substituted in one ormore places in the same way or differently with hydroxy, halogen, amino,C₁₋₆-alkoxy, or with the group —NHC₁₋₆-alkyl or —N-di-C₁₋₆-alkyl, or R³and R⁵ together form a C₃-C₁₂-cycloalkyl ring or a C₃-C₁₂-cycloalkenylring, which optionally can be substituted in one or more places in thesame way or differently with hydroxy, halogen, amino, C₁₋₆-alkoxy, orwith the group —NHC₁₋₆-alkyl or —N-di-C₁₋₆-alkyl, R⁶ and R⁷ are the sameor different and stand for hydrogen, linear or branched C₁-C₆-alkyl,C₂-C₆-alkenyl or C₂-C₆-alkinyl, which optionally can be substituted inone or more places in the same way or differently with hydroxy, halogen,amino, C₁₋₆-alkoxy, or with the group —NHC₁₋₆-alkyl or —N-di-C₁₋₆-alkyl,or together form a C₃-C₁₂-cycloalkyl ring or a C₃-C₁₂-cycloalkenyl ring,which optionally can be substituted in one or more places in the sameway or differently with hydroxy, halogen, amino, C₁₋₆-alkoxy, or withthe group —NHC₁₋₆-alkyl or —N-di-C₁₋₆-alkyl, or R⁵ and R⁶ optionallytogether form a double bond, T stands for —CH₂—, —O—, —CH₂═CH₂—,—CH≡CH—, —CH₂—O—CH₂—, —CH₂—O—, —O—CH₂— or ═CO, and n stands for 0-6, aswell as tautomers, isomers and salts thereof.
 3. Compounds of generalformula I, according to claims 1 and 2, in which R¹ stands for linear orbranched C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl, C₁-C₆-alkoxy,C₁-C₆-alkylthio or C₃-C₁₂-cycloalkyl, C₃-C₁₂-cycloalkenyl,C₃-C₁₂-heterocycloalkyl, C₃-C₁₂-heterocycloalkenyl, aryl or heteroaryl,which optionally can be substituted in one or more places in the sameway or differently with hydroxy, halogen, amino, C₁₋₆-alkyl,C₁₋₆-alkoxy, C₁₋₆-alkylthio, halo-C₁₋₆-alkyl, halo-C₁₋₆-alkoxy,C₁₋₆-alkoxycarbonyl, cyano, nitro, C₁₋₆-alkylsulfanyl,C₁₋₆-alkylsulfinyl, C₁₋₆-alkylsulfonyl, or with the group—C(O)C₁₋₆-alkyl, —NHC₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, —CONH₂,—CONHC₁₋₆-alkyl or —CON-di-C₁₋₆-alkyl, or can be substituted withanother aryl or heteroaryl radical, which optionally itself can besubstituted in one or more places in the same way or differently withhydroxy, halogen, amino, C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio,halo-C₁₋₆-alkyl, halo-C₁₋₆-alkoxy, C₁₋₆-alkoxycarbonyl, cyano, nitro,C₁₋₆-alkylcarbonyl, C₁₋₆-alkylsulfanyl, C₁₋₆-alkylsulfinyl,C₁₋₆-alkylsulfonyl, or with the group —C(O)C₁₋₆-alkyl, —NHC₁₋₆-alkyl,—N-di-C₁₋₆-alkyl, —CONH₂, —CONHC₁₋₆-alkyl or —CON-di-C₁₋₆-alkyl, R² andR³ are the same or different and stand for hydrogen, linear or branchedC₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl or C₁-C₆-alkoxy, whichoptionally can be substituted in one or more places in the same way ordifferently with hydroxy, halogen, amino, C₁₋₆-alkoxy, or with the group—NHC₁₋₆-alkyl or —N-di-C₁₋₆-alkyl, R⁴ and R⁵ are the same or differentand stand for hydrogen, halogen, linear or branched C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkinyl or C₁-C₆-alkoxy, which optionally can besubstituted in one or more places in the same way or differently withhydroxy, halogen, amino, C₁₋₆-alkoxy, or with the group —NHC₁₋₆-alkyl or—N-di-C₁₋₆-alkyl, or together stand for a carbonyl group, or togetherform a cyclic five- or six-ring-acetal of the structure

 or R² and R⁴ together form a C₃-C₁₂-cycloalkyl ring or aC₃-C₁₂-cycloalkenyl ring, which optionally can be substituted in one ormore places in the same way or differently with hydroxy, halogen, amino,C₁₋₆-alkoxy, or with the group —NHC₁₋₆-alkyl or —N-di-C₁₋₆-alkyl, or R³and R⁵ together form a C₃-C₁₂-cycloalkyl ring or a C₃-C₁₂-cycloalkenylring, which optionally can be substituted in one or more places in thesame way or differently with hydroxy, halogen, amino, C₁₋₆-alkoxy, orwith the group —NHC₁₋₆-alkyl or —N-di-C₁₋₆-alkyl, R⁶ and R⁷ are the sameor different and stand for hydrogen, linear or branched C₁-C₆-alkyl,C₂-C₆-alkenyl or C₂-C₆-alkinyl, which optionally can be substituted inone or more places in the same way or differently with hydroxy, halogen,amino, C₁₋₆-alkoxy, or with the group —NHC₁₋₆-alkyl or —N-di-C₁₋₆-alkyl,or together form a C₃-C₁₂-cycloalkyl ring or a C₃-C₁₂-cycloalkenyl ring,which optionally can be substituted in one or more places in the sameway or differently with hydroxy, halogen, amino, C₁₋₆-alkoxy, or withthe group —NHC₁₋₆-alkyl or —N-di-C₁₋₆-alkyl, or R⁵ and R⁶ optionallytogether form a double bond, T stands for —CH₂—, —O—, —CH₂═CH₂—,—CH≡CH—, —CH₂—O—CH₂—, —CH₂—O—, —O—CH₂— or ═CO, and n stands for 0-6, aswell as tautomers, isomers and salts thereof.
 4. Compounds of generalformula I, according to claims 1 to 3, in which R¹ stands for linear orbranched C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl, C₁-C₆-alkoxy,C₁-C₆-alkylthio or cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, adamantanyl,cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl,cyclononenyl or cyclodecenyl, oxiranyl, oxethanyl, aziridinyl,azetidinyl, tetrahydrofuranyl, pyrrolidinyl, dioxolanyl, imidazolidinyl,pyrazolidinyl, dioxanyl, piperidinyl, morpholinyl, dithianyl,thiomorpholinyl, piperazinyl, trithianyl, quinuclidinyl, pyrrolinyl,imidazolinyl, pyrazolinyl, pyranyl, thiinyl, dihydroazetyl,cyclopropenyl, cyclopentadienyl, phenyl, tropyl, cyclooctadienyl,indenyl, naphthyl, biphenyl, azulenyl, fluorenyl, anthracenyl, thienyl,furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl,benzofuranyl, benzothienyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, triazinyl, oxepinyl, azocinyl, indolizinyl, indolyl,isoindolyl, indazolyl, benzimidazolyl, purinyl, quinolinyl,isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl,phenothiazinyl, 1,3-benzodioxol-5-yl, phenoxazinyl or xanthenyl, whichoptionally can be substituted in one or more places in the same way ordifferently with hydroxy, halogen, amino, C₁₋₆-alkyl, C₁₋₆-alkoxy,C₁₋₆-alkylthio, halo-C₁₋₆-alkyl, halo-C₁₋₆-alkoxy, C₁₋₆-alkoxycarbonyl,cyano, nitro, C₁₋₆-alkylsulfanyl, C₁₋₆-alkylsulfinyl,C₁₋₆-alkylsulfonyl, or can be substituted with the group—C(O)C₁₋₆-alkyl, —NHC₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, —CONH₂,—CONHC₁₋₆-alkyl or —CON-di-C₁₋₆-alkyl, or can be substituted withanother aryl or heteroaryl radical, which optionally itself can besubstituted in one or more places in the same way or differently withhydroxy, halogen, amino, C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio,halo-C₁₋₆-alkyl, halo-C₁₋₆-alkoxy, C₁₋₆-alkoxycarbonyl, cyano, nitro,C₁₋₆-alkylcarbonyl, C₁₋₆-alkylsulfanyl, C₁₋₆-alkylsulfinyl,C₁₋₆-alkylsulfonyl, or with the group —C(O)C₁₋₆-alkyl, —NHC₁₋₆-alkyl,—N-di-C₁₋₆-alkyl, —CONH₂, —CONHC₁-alkyl or —CON-di-C₁₋₆-alkyl, R² and R³are the same or different and stand for hydrogen, linear or branchedC₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkinyl or C₁-C₆-alkoxy, whichoptionally can be substituted in one or more places in the same way ordifferently with hydroxy, halogen, amino, C₁₋₆-alkoxy, or with the group—NHC₁₋₆-alkyl or —N-di-C₁₋₆-alkyl, R⁴ and R⁵ are the same or differentand stand for hydrogen, halogen, linear or branched C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkinyl or C₁-C₆-alkoxy, which optionally can besubstituted in one or more places in the same way or differently withhydroxy, halogen, amino, C₁₋₆-alkoxy, or with the group —NHC₁₋₆-alkyl or—N-di-C₁₋₆-alkyl, or together stand for a carbonyl group, or togetherform a cyclic five- or six-ring-acetal of the structure

 or R² and R⁴ together form a C₃-C₇-cycloalkyl ring or aC₃-C₇-cycloalkenyl ring, which optionally can be substituted in one ormore places in the same way or differently with hydroxy, halogen, amino,C₁₋₆-alkoxy, or with the group —NHC₁₋₆-alkyl or —N-di-C₁₋₆-alkyl, or R³and R⁵ together form a C₃-C₇-cycloalkyl ring or a C₃-C₇-cycloalkenylring, which optionally can be substituted in one or more places in thesame way of differently with hydroxy, halogen, amino, C₁₋₆-alkoxy, orwith the group —NHC₁₋₆-alkyl or —N-di-C₁₋₆-alkyl, R⁶ and R⁷ are the sameor different and stand for hydrogen, linear or branched C₁-C₆-alkyl,C₂-C₆-alkenyl or C₂-C₆-alkinyl, which optionally can be substituted inone or more places in the same way or differently with hydroxy, halogen,amino, C₁₋₆-alkoxy, or with the group —NHC₁₋₆-alkyl or —N-di-C₁₋₆-alkyl,or together form a C₃-C₇-cycloalkyl ring or a C₃-C₇-cycloalkenyl ring,which optionally can be substituted in one or more places in the sameway or differently with hydroxy, halogen, amino, C₁₋₆-alkoxy, or withthe group —NHC₁₋₆-alkyl or —N-di-C₁₋₆-alkyl, or R⁵ and R⁶ optionallytogether form a double bond, T stands for —CH₂—, —O—, —CH₂═CH₂—,—CH≡CH—, —CH₂—O—CH₂—, —CH₂—O—, —O—CH₂— or ═CO, and n stands for 0-6, aswell as tautomers, isomers and salts thereof.
 5. Compounds of generalformula I, according to claims 1 to 4, in which R¹ stands forC₁-C₆-alkylthio, phenyl, biphenyl, thienyl, cyclopropyl, cyclohexyl,pyridyl, naphthyl, 1,3-benzodioxol-5-yl or isoxazolyl, which optionallycan be substituted in one or more places in the same way or differentlywith halogen, amino, cyano, C₁₋₆-alkyl-sulfonyl, C₁₋₆-alkyl,halo-C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, or with the group—C(O)C₁₋₆-alkyl, or which can be substituted with phenyl, thienyl,naphthyl, pyridyl, furanyl or pyrimidinyl, which optionally itself canbe substituted in one or more places in the same way or differently withC₁₋₆-alkyl, C₁₋₆-alkoxy, amino, C₁₋₆-alkylsulfonyl, cyano or with thegroup —C(O)NH₂, R², R³, R⁴, R⁵, R⁶ and R⁷ stand for hydrogen orC₁₋₆-alkyl, T stands for the group —CH₂—, —CH₂—O—CH₂— or —CH₂—O—, and nstands for 0-2, as well as tautomers, isomers and salts thereof. 6.Compounds of general formula II

in which R², R³, R⁴, R⁵, R⁶ and R⁷ have the meanings that are indicatedin general formula I, as intermediate products for the production of thecompounds of general formula I according to the invention.
 7. Use of thecompounds of general formula I, according to claims 1 to 5, for theproduction of a pharmaceutical agent for treating cancer, auto-immunediseases, chemotherapy-agent-induced alopecia and mucositis,cardiovascular diseases, infectious diseases, nephrological diseases,chronic and acute neurodegenerative diseases and viral infections. 8.Use according to claim 7, wherein cancer is defined as solid tumors andleukemia; auto-immune diseases are defined as psoriasis, alopecia andmultiple sclerosis; cardiovascular diseases are defined as stenoses,arterioscleroses and restenoses; infectious diseases are defined asdiseases that are caused by unicellular parasites; nephrologicaldiseases are defined as glomerulonephritis; chronic neurodegenerativediseases are defined as Huntington's disease, amyotrophic lateralsclerosis, Parkinson's disease, AIDS dementia and Alzheimer's disease;acute neurodegenerative diseases are defined as ischemias of the brainand neurotraumas; and viral infections are defined as cytomegalicinfections, herpes, Hepatitis B and C, and HIV diseases. 9.Pharmaceutical agents that contain at least one compound according toclaims 1 to
 5. 10. Pharmaceutical agents according to claim 9 fortreating cancer, auto-immune diseases, cardiovascular diseases,infectious diseases, nephrological diseases, neurodegenerative diseasesand viral infections.
 11. Compounds according to claims 1 to 5 andpharmaceutical agents according to claims 9 and 10 with suitableformulation substances and vehicles.
 12. Use of the compounds of generalformula I, according to claims 1 to 5, as inhibitors of thecyclin-dependent kinases.
 13. Use according to claim 12, wherein thekinase is CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 or CDK9. 14.Use of the compounds of general formula I, according to claims 1 to 5,as inhibitors of glycogen-synthase-kinase (GSK-3β).
 15. Use of thecompounds of general formula I, according to claims 1 to 5, in the formof a pharmaceutical preparation for enteral, parenteral and oraladministration.